RU2010112967A - COMPOUNDS MODELING EXTRACELLULAR CALCIUM - Google Patents

COMPOUNDS MODELING EXTRACELLULAR CALCIUM Download PDF

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RU2010112967A
RU2010112967A RU2010112967/04A RU2010112967A RU2010112967A RU 2010112967 A RU2010112967 A RU 2010112967A RU 2010112967/04 A RU2010112967/04 A RU 2010112967/04A RU 2010112967 A RU2010112967 A RU 2010112967A RU 2010112967 A RU2010112967 A RU 2010112967A
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thiophene
carboxylic acid
chlorophenyl
phenyl
fluorobenzamido
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RU2465272C2 (en
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Гонул ВЕЛИСЕЛЕБИ (US)
Гонул ВЕЛИСЕЛЕБИ
Кеннет А. СТОДЕРМАН (US)
Кеннет А. СТОДЕРМАН
Дэвид П.М. ПЛЕЙНЕТ (US)
Дэвид П.М. ПЛЕЙНЕТ
Соан ЧЕНГ (US)
Соан ЧЕНГ
Джеффри П. УИТТЕН (US)
Джеффри П. УИТТЕН
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КалсиМедика, Инк. (US)
КалсиМедика, Инк.
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Abstract

1. Соединение формулы (I) или его фармацевтически приемлемая соль, либо фармацевтически приемлемое пролекарство ! ! где R1 представляет собой водород, C1-С6 алкил, C1-С6 галогеноалкил или бензил; ! R2 представляет собой арил, бензотиенил, бензофуранил или группу -СН2СН2-фенил; где R2 возможно замещен 1 или 2 заместителями, независимо выбранными из F, Cl, Br, I, -CN, -NO2, -ОН, -СF3, -ОСF3, -OR8, C1-С6 алкила, С3-С6 циклоалкила, С1-С6 гетероалкила, С1-С6 галогеноалкила, тетразолила, C2-С6 гетероциклоалкила, фенила, -NHS(=O)2R8, -S(=O)2N(R9)2, -С(=O)СF3, -C(=O)NHS(=O)2R8, -S(=O)2NHC(=O)R8, -N(R9)2, -N(R9)C(=O)R8, -CO2R9, -C(=O)R8, -OC(=O)R8, -CON(R9)2, -SR8, -S(=O)R8 и -S(=O)2R8; ! R4 представляет собой арил, возможно замещенный 1 или 2 заместителями, независимо выбранными из F, Cl, Br, I, -CN, -NO2, -СF3, -ОН, -OR8, -ОСF3, C1-С6 алкила, С3-С6 циклоалкила, С1-С6 фторалкила, С1-С6 гетероалкила, C1-С6 галогеноалкила, тетразолила, С2-С6 гетероциклоалкила, фенила, -NHS(=O)2R8, S(=O)2N(R9)2, -С(=O)СF3, -C(=O)NHS(=O)2R8, -S(=O)2NHC(=O)R9, N(R9)2, -N(R9)C(=O)R8, -CO2R9, -C(=O)R8, -OC(=O)R8, -C(=O)N(R9)2, -SR8, -S(=O)R8 и -S(=O)2R8; ! каждый R8 независимо выбран из C1-С6 алкила, C1-С6 галогеноалкила, С3-С8 циклоалкила, фенила и бензила и ! каждый R9 независимо выбран из Н, С1-С6 алкила, C1-С6 галогеноалкила, С3-С8 циклоалкила, фенила и бензила. ! 2. Соединение по п.1, где R1 представляет собой водород. ! 3. Соединение по п.1, где R2 представляет собой бензотиенил, возможно замещенный 1 или 2 заместителями, выбранными из F, Cl, Br, I, ОН, СН3, СF3 и CN. ! 4. Соединение по п.3, где бензотиенил присоединен по положению 3. ! 5. Соединение по п.3, где бензотиенил присоединен по положению 5. ! 6. Соединение по п.1, где R4 представляет собой арильную группу. ! 7. Соединение по п.6, где арильная группа представляет собой фенил. ! 8. Соединение по п.7, где фенил замещен 1 или 2 заместителями, выбр 1. The compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable prodrug! ! where R1 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl or benzyl; ! R 2 represents aryl, benzothienyl, benzofuranyl or the group —CH 2 CH 2 phenyl; where R2 is optionally substituted with 1 or 2 substituents independently selected from F, Cl, Br, I, —CN, —NO2, —OH, —CF3, —OCF3, —OR8, C1-C6 alkyl, C3-C6 cycloalkyl, C1- C6 heteroalkyl, C1-C6 haloalkyl, tetrazolyl, C2-C6 heterocycloalkyl, phenyl, -NHS (= O) 2R8, -S (= O) 2N (R9) 2, -C (= O) CF3, -C (= O ) NHS (= O) 2R8, -S (= O) 2NHC (= O) R8, -N (R9) 2, -N (R9) C (= O) R8, -CO2R9, -C (= O) R8 , -OC (= O) R8, -CON (R9) 2, -SR8, -S (= O) R8 and -S (= O) 2R8; ! R4 is aryl, optionally substituted with 1 or 2 substituents independently selected from F, Cl, Br, I, —CN, —NO2, —CF3, —OH, —OR8, —OCF3, C1-C6 alkyl, C3-C6 cycloalkyl , C1-C6 fluoroalkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, tetrazolyl, C2-C6 heterocycloalkyl, phenyl, -NHS (= O) 2R8, S (= O) 2N (R9) 2, -C (= O) CF3, -C (= O) NHS (= O) 2R8, -S (= O) 2NHC (= O) R9, N (R9) 2, -N (R9) C (= O) R8, -CO2R9, - C (= O) R8, -OC (= O) R8, -C (= O) N (R9) 2, -SR8, -S (= O) R8 and -S (= O) 2R8; ! each R8 is independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, phenyl and benzyl and! each R9 is independently selected from H, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, phenyl, and benzyl. ! 2. The compound according to claim 1, where R1 represents hydrogen. ! 3. The compound according to claim 1, where R2 is benzothienyl, optionally substituted with 1 or 2 substituents selected from F, Cl, Br, I, OH, CH3, CF3 and CN. ! 4. The compound according to claim 3, where benzothienyl is attached at position 3.! 5. The compound according to claim 3, where benzothienyl is attached at position 5.! 6. The compound according to claim 1, where R4 represents an aryl group. ! 7. The compound according to claim 6, where the aryl group is phenyl. ! 8. The compound according to claim 7, where phenyl is substituted with 1 or 2 substituents, selected

Claims (15)

1. Соединение формулы (I) или его фармацевтически приемлемая соль, либо фармацевтически приемлемое пролекарство1. The compound of formula (I) or its pharmaceutically acceptable salt, or a pharmaceutically acceptable prodrug
Figure 00000001
Figure 00000001
 где R1 представляет собой водород, C1-С6 алкил, C1-С6 галогеноалкил или бензил;where R 1 represents hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl or benzyl; R2 представляет собой арил, бензотиенил, бензофуранил или группу -СН2СН2-фенил; где R2 возможно замещен 1 или 2 заместителями, независимо выбранными из F, Cl, Br, I, -CN, -NO2, -ОН, -СF3, -ОСF3, -OR8, C1-С6 алкила, С3-С6 циклоалкила, С1-С6 гетероалкила, С1-С6 галогеноалкила, тетразолила, C2-С6 гетероциклоалкила, фенила, -NHS(=O)2R8, -S(=O)2N(R9)2, -С(=O)СF3, -C(=O)NHS(=O)2R8, -S(=O)2NHC(=O)R8, -N(R9)2, -N(R9)C(=O)R8, -CO2R9, -C(=O)R8, -OC(=O)R8, -CON(R9)2, -SR8, -S(=O)R8 и -S(=O)2R8;R 2 represents aryl, benzothienyl, benzofuranyl or a —CH 2 CH 2 phenyl group; where R 2 is optionally substituted with 1 or 2 substituents independently selected from F, Cl, Br, I, —CN, —NO 2 , —OH, —CF 3 , —OCF 3 , —OR 8 , C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 haloalkyl, tetrazolyl, C 2 -C 6 heterocycloalkyl, phenyl, -NHS (= O) 2 R 8 , -S (= O) 2 N (R 9 ) 2 , -C (= O) CF 3 , -C (= O) NHS (= O) 2 R 8 , -S (= O) 2 NHC (= O) R 8 , -N (R 9 ) 2 , -N (R 9 ) C (= O) R 8 , -CO 2 R 9 , -C (= O) R 8 , -OC (= O) R 8 , -CON (R 9 ) 2 , - SR 8 , -S (= O) R 8 and -S (= O) 2 R 8 ; R4 представляет собой арил, возможно замещенный 1 или 2 заместителями, независимо выбранными из F, Cl, Br, I, -CN, -NO2, -СF3, -ОН, -OR8, -ОСF3, C1-С6 алкила, С3-С6 циклоалкила, С1-С6 фторалкила, С1-С6 гетероалкила, C1-С6 галогеноалкила, тетразолила, С2-С6 гетероциклоалкила, фенила, -NHS(=O)2R8, S(=O)2N(R9)2, -С(=O)СF3, -C(=O)NHS(=O)2R8, -S(=O)2NHC(=O)R9, N(R9)2, -N(R9)C(=O)R8, -CO2R9, -C(=O)R8, -OC(=O)R8, -C(=O)N(R9)2, -SR8, -S(=O)R8 и -S(=O)2R8;R 4 is aryl, optionally substituted with 1 or 2 substituents independently selected from F, Cl, Br, I, —CN, —NO 2 , —CF 3 , —OH, —OR 8 , —OCF 3 , C 1 —C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 fluoroalkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 haloalkyl, tetrazolyl, C 2 -C 6 heterocycloalkyl, phenyl, -NHS (= O) 2 R 8 , S (= O) 2 N (R 9 ) 2 , -C (= O) CF 3 , -C (= O) NHS (= O) 2 R 8 , -S (= O) 2 NHC (= O ) R 9 , N (R 9 ) 2 , -N (R 9 ) C (= O) R 8 , -CO 2 R 9 , -C (= O) R 8 , -OC (= O) R 8 , - C (= O) N (R 9 ) 2 , -SR 8 , -S (= O) R 8 and -S (= O) 2 R 8 ; каждый R8 независимо выбран из C1-С6 алкила, C1-С6 галогеноалкила, С3-С8 циклоалкила, фенила и бензила иeach R 8 is independently selected from C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, phenyl, and benzyl; and каждый R9 независимо выбран из Н, С1-С6 алкила, C1-С6 галогеноалкила, С3-С8 циклоалкила, фенила и бензила.each R 9 is independently selected from H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, phenyl, and benzyl. 2. Соединение по п.1, где R1 представляет собой водород.2. The compound according to claim 1, where R 1 represents hydrogen. 3. Соединение по п.1, где R2 представляет собой бензотиенил, возможно замещенный 1 или 2 заместителями, выбранными из F, Cl, Br, I, ОН, СН3, СF3 и CN.3. The compound according to claim 1, where R 2 represents benzothienyl, possibly substituted by 1 or 2 substituents selected from F, Cl, Br, I, OH, CH 3 , CF 3 and CN. 4. Соединение по п.3, где бензотиенил присоединен по положению 3.4. The compound according to claim 3, where the benzothienyl is attached at position 3. 5. Соединение по п.3, где бензотиенил присоединен по положению 5.5. The compound according to claim 3, where the benzothienyl is attached at position 5. 6. Соединение по п.1, где R4 представляет собой арильную группу.6. The compound according to claim 1, where R 4 represents an aryl group. 7. Соединение по п.6, где арильная группа представляет собой фенил.7. The compound according to claim 6, where the aryl group is phenyl. 8. Соединение по п.7, где фенил замещен 1 или 2 заместителями, выбранными из F, Cl, Вr, I, ОН, СН3, СF3 и CN.8. The compound according to claim 7, where phenyl is substituted by 1 or 2 substituents selected from F, Cl, Br, I, OH, CH 3 , CF 3 and CN. 9. Фармацевтическая композиция, содержащая соединение формулы (I), или его фармацевтически приемлемую соль, или фармацевтически приемлемое пролекарство9. A pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable prodrug
Figure 00000002
Figure 00000002
 где R1 представляет собой водород, C1-С6 алкил, C1-С6 галогеноалкил или бензил;where R 1 represents hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl or benzyl; R2 представляет собой арил, бензотиенил, бензофуранил или группу -СН2СН2-фенил; где R2 возможно замещен 1 или 2 заместителями, независимо выбранными из F, Cl, Вr, I, -CN, -NO2, -ОН, -СF3, -ОСF3, -OR8, C1-С6 алкила, С3-С6 циклоалкила, C1-С6 гетероалкила, C1-C6 галогеноалкила, тетразолила, C2-С6 гетероциклоалкила, фенила, -NHS(=O)2R8, -S(=O)2N(R9)2, -С(=O)СF3, -C(=O)NHS(=O)2R8, -S(=O)2NHC(=O)R8, -N(R9)2, -N(R9)C(=O)R8, -CO2R9, -C(=O)R8, -OC(=O)R8, -CON(R9)2, -SR8, -S(=O)R8 и -S(=O)2R8;R 2 represents aryl, benzothienyl, benzofuranyl or a —CH 2 CH 2 phenyl group; wherein R 2 is optionally substituted with 1 or 2 substituents independently selected from F, Cl, Br, I, —CN, —NO 2 , —OH, —CF 3 , —OCF 3 , —OR 8 , C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 haloalkyl, tetrazolyl, C 2 -C 6 heterocycloalkyl, phenyl, -NHS (= O) 2 R 8 , -S (= O) 2 N (R 9 ) 2 , -C (= O) CF 3 , -C (= O) NHS (= O) 2 R 8 , -S (= O) 2 NHC (= O) R 8 , -N (R 9 ) 2 , -N (R 9 ) C (= O) R 8 , -CO 2 R 9 , -C (= O) R 8 , -OC (= O) R 8 , -CON (R 9 ) 2 , - SR 8 , -S (= O) R 8 and -S (= O) 2 R 8 ; R4 представляет собой арил, возможно замещенный 1 или 2 заместителями, независимо выбранными из F, Cl, Br, I, -CN, -NO2, -СF3, -ОН, -OR8, -ОСF3, C1-С6 алкила, С3-С6 циклоалкила, C1-С6 фторалкила, С1-С6 гетероалкила,C1-С6 галогеноалкила, тетразолила, С2-С6 гетероциклоалкила, фенила, -NHS(=O)2R8, S(=O)2N(R9)2, -С(=O)СF3, -C(=O)NHS(=O)2R8, -S(=O)2NHC(=O)R9, N(R9)2, -N(R9)C(=O)R8, -CO2R9, -C(=O)R8, -OC(=O)R8, -C(=O)N(R9)2, -SR8, -S(=O)R8 и -S(=O)2R8;R 4 is aryl, optionally substituted with 1 or 2 substituents independently selected from F, Cl, Br, I, —CN, —NO 2 , —CF 3 , —OH, —OR 8 , —OCF 3 , C 1 —C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 fluoroalkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 haloalkyl, tetrazolyl, C 2 -C 6 heterocycloalkyl, phenyl, -NHS (= O) 2 R 8 , S (= O) 2 N (R 9 ) 2 , -C (= O) CF 3 , -C (= O) NHS (= O) 2 R 8 , -S (= O) 2 NHC (= O ) R 9 , N (R 9 ) 2 , -N (R 9 ) C (= O) R 8 , -CO 2 R 9 , -C (= O) R 8 , -OC (= O) R 8 , - C (= O) N (R 9 ) 2 , -SR 8 , -S (= O) R 8 and -S (= O) 2 R 8 ; каждый R8 независимо выбран из C1-С6 алкила, C1-С6 галогеноалкила, С3-С8 циклоалкила, фенила и бензила иeach R 8 is independently selected from C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, phenyl, and benzyl; and каждый R9 независимо выбран из Н, C1-С6 алкила, С1-С6 галогеноалкила, С3-С8 циклоалкила, фенила и бензила;each R 9 is independently selected from H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, phenyl, and benzyl; и фармацевтически приемлемый разбавитель, эксципиент или связуающее вещество.and a pharmaceutically acceptable diluent, excipient or binder. 10. Соединение, выбранное из:10. A compound selected from: 2-(4-фторбензамидо)-4-(4-хлорфенил)тиофен-3-карбоновой кислоты;2- (4-fluorobenzamido) -4- (4-chlorophenyl) thiophene-3-carboxylic acid; 2-(4-фторбензамидо)-4-(3,4-дихлорфенил)тиофен-3-карбоновой кислоты;2- (4-fluorobenzamido) -4- (3,4-dichlorophenyl) thiophene-3-carboxylic acid; 2-(4-фторбензамидо)-4-(4-трифторметилфенил)тиофен-3-карбоновой кислоты;2- (4-fluorobenzamido) -4- (4-trifluoromethylphenyl) thiophene-3-carboxylic acid; 2-(4-фторбензамидо)-4-(2-бромфенил)тиофен-3-карбоновой кислоты;2- (4-fluorobenzamido) -4- (2-bromophenyl) thiophene-3-carboxylic acid; 2-(4-фторбензамидо)-4-(3,4-диметилфенил)тиофен-3-карбоновой кислоты;2- (4-fluorobenzamido) -4- (3,4-dimethylphenyl) thiophene-3-carboxylic acid; 2-(4-фторбензамидо)-4-(2-хлорфенил)тиофен-3-карбоновой кислоты;2- (4-fluorobenzamido) -4- (2-chlorophenyl) thiophene-3-carboxylic acid; 2-(4-фторбензамидо)-4-(2,4-дихлорфенил)тиофен-3-карбоновой кислоты;2- (4-fluorobenzamido) -4- (2,4-dichlorophenyl) thiophene-3-carboxylic acid; 2-(4-фторбензамидо)-4-(фенил)тиофен-3-карбоновой кислоты;2- (4-fluorobenzamido) -4- (phenyl) thiophene-3-carboxylic acid; 2-(4-фторбензамидо)-4-(4-метилфенил)тиофен-3-карбоновой кислоты;2- (4-fluorobenzamido) -4- (4-methylphenyl) thiophene-3-carboxylic acid; 2-(3-фторбензамидо)-4-(4-бромфенил)тиофен-3-карбоновой кислоты;2- (3-fluorobenzamido) -4- (4-bromophenyl) thiophene-3-carboxylic acid; 2-(4-хлорбензамидо)-4-(4-бромфенил)тиофен-3-карбоновой кислоты;2- (4-chlorobenzamido) -4- (4-bromophenyl) thiophene-3-carboxylic acid; 2-(4-йодбензамидо)-4-(2,4-дихлорфенил)тиофен-3-карбоновой кислоты;2- (4-iodobenzamido) -4- (2,4-dichlorophenyl) thiophene-3-carboxylic acid; 2-(бензотиен-2-иламидо)-4-(4-бромфенил)тиофен-3-карбоновой кислоты;2- (benzothien-2-ylamido) -4- (4-bromophenyl) thiophene-3-carboxylic acid; 2-(3-метилбензамидо)-4-(4-бромфенил)тиофен-3-карбоновой кислоты;2- (3-methylbenzamido) -4- (4-bromophenyl) thiophene-3-carboxylic acid; 2-(4-бромбензамидо)-4-(4-метилфенил)тиофен-3-карбоновой кислоты;2- (4-bromobenzamido) -4- (4-methylphenyl) thiophene-3-carboxylic acid; 2-(4-бромбензамидо)-4-(4-хлорфенил)тиофен-3-карбоновой кислоты;2- (4-bromobenzamido) -4- (4-chlorophenyl) thiophene-3-carboxylic acid; 2-(4-бромбензамидо)-4-(4-бромфенил)тиофен-3-карбоновой кислоты;2- (4-bromobenzamido) -4- (4-bromophenyl) thiophene-3-carboxylic acid; 2-(4-бромбензамидо)-4-(3,5-дихлорфенил)тиофен-3-карбоновой кислоты;2- (4-bromobenzamido) -4- (3,5-dichlorophenyl) thiophene-3-carboxylic acid; 2-(4-бромбензамидо)-4-(3-хлорфенил)тиофен-3-карбоновой кислоты;2- (4-bromobenzamido) -4- (3-chlorophenyl) thiophene-3-carboxylic acid; 2-(4-бромбензамидо)-4-(3,4-диметилфенил)тиофен-3-карбоновой кислоты;2- (4-bromobenzamido) -4- (3,4-dimethylphenyl) thiophene-3-carboxylic acid; 2-(4-бромбензамидо)-4-(4-трифторметилфенил)тиофен-3-карбоновой кислоты;2- (4-bromobenzamido) -4- (4-trifluoromethylphenyl) thiophene-3-carboxylic acid; 2-(4-бромбензамидо)-4-(3,4-дихлорфенил)тиофен-3-карбоновой кислоты;2- (4-bromobenzamido) -4- (3,4-dichlorophenyl) thiophene-3-carboxylic acid; 2-(4-бромбензамидо)-4-(2-бромфенил)тиофен-3-карбоновой кислоты;2- (4-bromobenzamido) -4- (2-bromophenyl) thiophene-3-carboxylic acid; 2-(3-фторбензамидо)-4-(4-хлорфенил)тиофен-3-карбоновой кислоты;2- (3-fluorobenzamido) -4- (4-chlorophenyl) thiophene-3-carboxylic acid; 2-(3-фторбензамидо)-4-(2,4-дихлорфенил)тиофен-3-карбоновой кислоты;2- (3-fluorobenzamido) -4- (2,4-dichlorophenyl) thiophene-3-carboxylic acid; 2-(3-фторбензамидо)-4-(3,4-диметилфенил)тиофен-3-карбоновой кислоты;2- (3-fluorobenzamido) -4- (3,4-dimethylphenyl) thiophene-3-carboxylic acid; 2-(3-фторбензамидо)-4-(3-хлорфенил)тиофен-3-карбоновой кислоты;2- (3-fluorobenzamido) -4- (3-chlorophenyl) thiophene-3-carboxylic acid; 2-(3-фторбензамидо)-4-(4-метилфенил)тиофен-3-карбоновой кислоты;2- (3-fluorobenzamido) -4- (4-methylphenyl) thiophene-3-carboxylic acid; 2-(3-фторбензамидо)-4-(3,4-дихлорфенил)тиофен-3-карбоновой кислоты;2- (3-fluorobenzamido) -4- (3,4-dichlorophenyl) thiophene-3-carboxylic acid; 2-(3-фторбензамидо)-4-(2-бромфенил)тиофен-3-карбоновой кислоты;2- (3-fluorobenzamido) -4- (2-bromophenyl) thiophene-3-carboxylic acid; 2-(3-фторбензамидо)-4-(4-трифторметилфенил)тиофен-3-карбоновой кислоты;2- (3-fluorobenzamido) -4- (4-trifluoromethylphenyl) thiophene-3-carboxylic acid; 2-(4-хлорбензамидо)-4-(4-хлорфенил)тиофен-3-карбоновой кислоты;2- (4-chlorobenzamido) -4- (4-chlorophenyl) thiophene-3-carboxylic acid; 2-(4-хлорбензамидо)-4-(4-метилфенил)тиофен-3-карбоновой кислоты;2- (4-chlorobenzamido) -4- (4-methylphenyl) thiophene-3-carboxylic acid; 2-(4-хлорбензамидо)-4-(2,4-дихлорфенил)тиофен-3-карбоновой кислоты;2- (4-chlorobenzamido) -4- (2,4-dichlorophenyl) thiophene-3-carboxylic acid; 2-(4-хлорбензамидо)-4-(4-фторфенил)тиофен-3-карбоновой кислоты;2- (4-chlorobenzamido) -4- (4-fluorophenyl) thiophene-3-carboxylic acid; 2-(4-хлорбензамидо)-4-(3,4-дихлорфенил)тиофен-3-карбоновой кислоты;2- (4-chlorobenzamido) -4- (3,4-dichlorophenyl) thiophene-3-carboxylic acid; 2-(4-хлорбензамидо)-4-(3,4-диметилфенил)тиофен-3-карбоновой кислоты;2- (4-chlorobenzamido) -4- (3,4-dimethylphenyl) thiophene-3-carboxylic acid; 2-(4-хлорбензамидо)-4-(4-трифторметилфенил)тиофен-3-карбоновой кислоты;2- (4-chlorobenzamido) -4- (4-trifluoromethylphenyl) thiophene-3-carboxylic acid; 2-(4-хлорбензамидо)-4-(фенил)тиофен-3-карбоновой кислоты;2- (4-chlorobenzamido) -4- (phenyl) thiophene-3-carboxylic acid; 2-(4-хлорбензамидо)-4-(2-бромфенил)тиофен-3-карбоновой кислоты;2- (4-chlorobenzamido) -4- (2-bromophenyl) thiophene-3-carboxylic acid; 2-(4-хлорбензамидо)-4-(3-хлорфенил)тиофен-3-карбоновой кислоты;2- (4-chlorobenzamido) -4- (3-chlorophenyl) thiophene-3-carboxylic acid; 2-(бензотиен-2-иламидо)-4-(4-хлорфенил)тиофен-3-карбоновой кислоты;2- (benzothien-2-ylamido) -4- (4-chlorophenyl) thiophen-3-carboxylic acid; 2-(бензотиен-2-иламидо)-4-(4-метилфенил)тиофен-3-карбоновой кислоты;2- (benzothien-2-ylamido) -4- (4-methylphenyl) thiophen-3-carboxylic acid; 2-(бензотиен-2-иламидо)-4-(2,4-дихлорфенил)тиофен-3-карбоновой кислоты;2- (benzothien-2-ylamido) -4- (2,4-dichlorophenyl) thiophene-3-carboxylic acid; 2-(бензотиен-2-иламидо)-4-(3-хлорфенил)тиофен-3-карбоновой кислоты;2- (benzothien-2-ylamido) -4- (3-chlorophenyl) thiophene-3-carboxylic acid; 2-(бензотиен-2-иламидо)-4-(4-трифторметилфенил)тиофен-3-карбоновой кислоты;2- (benzothien-2-ylamido) -4- (4-trifluoromethylphenyl) thiophene-3-carboxylic acid; 2-(бензотиен-2-иламидо)-4-(2-бромфенил)тиофен-3-карбоновой кислоты;2- (benzothien-2-ylamido) -4- (2-bromophenyl) thiophene-3-carboxylic acid; 2-(бензотиен-2-иламидо)-4-(3,4-диметилфенил)тиофен-3-карбоновой кислоты;2- (benzothien-2-ylamido) -4- (3,4-dimethylphenyl) thiophene-3-carboxylic acid; 2-(3-метилбензамидо)-4-(4-хлорфенил)тиофен-3-карбоновой кислоты;2- (3-methylbenzamido) -4- (4-chlorophenyl) thiophene-3-carboxylic acid; 2-(3-метилбензамидо)-4-(4-метилфенил)тиофен-3-карбоновой кислоты;2- (3-methylbenzamido) -4- (4-methylphenyl) thiophene-3-carboxylic acid; 2-(3-метилбензамидо)-4-(фенил)тиофен-3-карбоновой кислоты;2- (3-methylbenzamido) -4- (phenyl) thiophene-3-carboxylic acid; 2-(3-метилбензамидо)-4-(2-бромфенил)тиофен-3-карбоновой кислоты;2- (3-methylbenzamido) -4- (2-bromophenyl) thiophene-3-carboxylic acid; 2-(3-метилбензамидо)-4-(4-фторфенил)тиофен-3-карбоновой кислоты;2- (3-methylbenzamido) -4- (4-fluorophenyl) thiophene-3-carboxylic acid; 2-(3-метилбензамидо)-4-(3-хлорфенил)тиофен-3-карбоновой кислоты;2- (3-methylbenzamido) -4- (3-chlorophenyl) thiophene-3-carboxylic acid; 2-(3-метилбензамидо)-4-(4-трифторметилфенил)тиофен-3-карбоновой кислоты;2- (3-methylbenzamido) -4- (4-trifluoromethylphenyl) thiophene-3-carboxylic acid; 2-(3-метилбензамидо)-4-(2,4-дихлорфенил)тиофен-3-карбоновой кислоты;2- (3-methylbenzamido) -4- (2,4-dichlorophenyl) thiophene-3-carboxylic acid; 2-(3-метилбензамидо)-4-(3,4-диметилфенил)тиофен-3-карбоновой кислоты;2- (3-methylbenzamido) -4- (3,4-dimethylphenyl) thiophene-3-carboxylic acid; метил-2-(4-хлорбензамидо)-4-(4-фторфенил)тиофен-3-карбоксилата;methyl 2- (4-chlorobenzamido) -4- (4-fluorophenyl) thiophene-3-carboxylate; этил-2-(4-хлорбензамидо)-4-(4-фторфенил)тиофен-3-карбоксилата;ethyl 2- (4-chlorobenzamido) -4- (4-fluorophenyl) thiophene-3-carboxylate; 2-(4-йодбензамидо)-4-(4-бромфенил)тиофен-3-карбоновой кислоты;2- (4-iodobenzamido) -4- (4-bromophenyl) thiophene-3-carboxylic acid; 4-(2,4-дихлорфенил)-2-(3-фенилпропанамидо)тиофен-3-карбоновой кислоты;4- (2,4-dichlorophenyl) -2- (3-phenylpropanamido) thiophene-3-carboxylic acid; 4-(3,4-дихлорфенил)-2-(3-фенилпропанамидо)тиофен-3-карбоновой кислоты;4- (3,4-dichlorophenyl) -2- (3-phenylpropanamido) thiophene-3-carboxylic acid; 4-(3,5-дихлорфенил)-2-(3-фенилпропанамидо)тиофен-3-карбоновой кислоты;4- (3,5-dichlorophenyl) -2- (3-phenylpropanamido) thiophene-3-carboxylic acid; 4-(4-хлорфенил)-2-(3-фенилпропанамидо)тиофен-3-карбоновой кислоты;4- (4-chlorophenyl) -2- (3-phenylpropanamido) thiophene-3-carboxylic acid; 4-(4-хлорфенил)-2-(3-(3-фторфенил)пропанамидо)тиофен-3-карбоновой кислоты;4- (4-chlorophenyl) -2- (3- (3-fluorophenyl) propanamido) thiophene-3-carboxylic acid; 4-(4-хлорфенил)-2-(3-(3-хлорфенил)пропанамидо)тиофен-3-карбоновой кислоты;4- (4-chlorophenyl) -2- (3- (3-chlorophenyl) propanamido) thiophene-3-carboxylic acid; 4-(3-хлорфенил)-2-(3-фенилпропанамидо)тиофен-3-карбоновой кислоты;4- (3-chlorophenyl) -2- (3-phenylpropanamido) thiophene-3-carboxylic acid; 4-(2-хлорфенил)-2-(3-фенилпропанамидо)тиофен-3-карбоновой кислоты;4- (2-chlorophenyl) -2- (3-phenylpropanamido) thiophene-3-carboxylic acid; 4-(4-бромфенил)-2-(2-хлор-4-фторбензамидо)тиофен-3-карбоновой кислоты;4- (4-bromophenyl) -2- (2-chloro-4-fluorobenzamido) thiophene-3-carboxylic acid; 4-(4-бромфенил)-2-(3,4-дифторбензамидо)тиофен-3-карбоновой кислоты;4- (4-bromophenyl) -2- (3,4-difluorobenzamido) thiophene-3-carboxylic acid; 2-(2-хлор-4-фторбензамидо)-4-(4-хлорфенил)тиофен-3-карбоновой кислоты;2- (2-chloro-4-fluorobenzamido) -4- (4-chlorophenyl) thiophene-3-carboxylic acid; 4-(4-бромфенил)-2-(2-фторбензамидо)тиофен-3-карбоновой кислоты;4- (4-bromophenyl) -2- (2-fluorobenzamido) thiophene-3-carboxylic acid; 4-(4-бромфенил)-2-(3-фтор-4-метоксибензамидо)тиофен-3-карбоновой кислоты;4- (4-bromophenyl) -2- (3-fluoro-4-methoxybenzamido) thiophene-3-carboxylic acid; 4-(4-хлорфенил)-2-(4-метилбензамидо)тиофен-3-карбоновой кислоты;4- (4-chlorophenyl) -2- (4-methylbenzamido) thiophene-3-carboxylic acid; 4-(4-бромфенил)-2-(4-цианобензамидо)тиофен-3-карбоновой кислоты;4- (4-bromophenyl) -2- (4-cyanobenzamido) thiophene-3-carboxylic acid; 4-(4-хлорфенил)-2-(4-этилбензамидо)тиофен-3-карбоновой кислоты;4- (4-chlorophenyl) -2- (4-ethylbenzamido) thiophene-3-carboxylic acid; 4-(4-хлорфенил)-2-(4-(трифторметил)бензамидо)тиофен-3-карбоновой кислоты;4- (4-chlorophenyl) -2- (4- (trifluoromethyl) benzamido) thiophene-3-carboxylic acid; 4-(4-хлорфенил)-2-(3-(3-фторфенил)пропанамидо)тиофен-3-карбоновой кислоты;4- (4-chlorophenyl) -2- (3- (3-fluorophenyl) propanamido) thiophene-3-carboxylic acid; 4-(4-бромфенил)-2-(3-(3-фторфенил)пропанамидо)тиофен-3-карбоновой кислоты;4- (4-bromophenyl) -2- (3- (3-fluorophenyl) propanamido) thiophene-3-carboxylic acid; 4-(4-хлорфенил)-2-(3-(2,4-дифторфенил)пропанамидо)тиофен-3-карбоновой кислоты;4- (4-chlorophenyl) -2- (3- (2,4-difluorophenyl) propanamido) thiophene-3-carboxylic acid; 4-(4-бромфенил)-2-(3-(4-фторфенил)пропанамидо)тиофен-3-карбоновой кислоты;4- (4-bromophenyl) -2- (3- (4-fluorophenyl) propanamido) thiophene-3-carboxylic acid; 4-(4-хлорфенил)-2-(3-(3,4-дифторфенил)пропанамидо)тиофен-3-карбоновой кислоты;4- (4-chlorophenyl) -2- (3- (3,4-difluorophenyl) propanamido) thiophene-3-carboxylic acid; 4-(4-бромфенил)-2-(3-(2,4-дифторфенил)пропанамидо)тиофен-3-карбоновой кислоты;4- (4-bromophenyl) -2- (3- (2,4-difluorophenyl) propanamido) thiophene-3-carboxylic acid; 4-(4-бромфенил)-2-(3-(3,4-дифторфенил)пропанамидо)тиофен-3-карбоновой кислоты;4- (4-bromophenyl) -2- (3- (3,4-difluorophenyl) propanamido) thiophene-3-carboxylic acid; 4-(4-хлорфенил)-2-(3-(4-фторфенил)пропанамидо)тиофен-3-карбоновой кислоты;4- (4-chlorophenyl) -2- (3- (4-fluorophenyl) propanamido) thiophene-3-carboxylic acid; 4-(4-хлорфенил)-2-(3-(3-хлорфенил)пропанамидо)тиофен-3-карбоновой кислоты и4- (4-chlorophenyl) -2- (3- (3-chlorophenyl) propanamido) thiophene-3-carboxylic acid and 4-(4-хлорфенил)-2-(3-(4-хлорфенил)пропанамидо)тиофен-3-карбоновой кислоты;4- (4-chlorophenyl) -2- (3- (4-chlorophenyl) propanamido) thiophene-3-carboxylic acid; или их фармацевтически приемлемой соли, или фармацевтически приемлемого пролекарства.or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable prodrug. 11. Способ лечения заболевания, расстройства или состояния у млекопитающего, включающий введение этому млекопитающему соединения формулы (I), или его фармацевтически приемлемой соли, или фармацевтически приемлемого пролекарства,11. A method of treating a disease, disorder or condition in a mammal, comprising administering to the mammal a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable prodrug,
Figure 00000003
Figure 00000003
 где R1 представляет собой водород, C1-С6 алкил, C1-С6 галогеноалкил или бензил;where R 1 represents hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl or benzyl; R2 представляет собой арил, бензотиенил, бензофуранил или группу -СН2СН2-фенил; где R2 возможно замещен 1 или 2 заместителями, независимо выбранными из F, Cl, Br, I, -CN, -NO2, -ОН, -СF3, -ОСF3, -OR8, C1-С6 алкила, С3-С6 циклоалкила, C1-С6 гетероалкила, С1-С6 галогеноалкила, тетразолила, С2-С6 гетероцикпоалкила, фенила, -NHS(=O)2R8, -S(=O)2N(R9)2, -С(=O)СF3, -C(=O)NHS(=O)2R8, -S(=O)2NHC(=O)R8, -N(R9)2, -N(R9)C(=O)R8, -CO2R9, -C(=O)R8, -OC(=O)R8, -C(=O)N(R9)2, -SR8, -S(=O)R8 и -S(=O)2R8;R 2 represents aryl, benzothienyl, benzofuranyl or a —CH 2 CH 2 phenyl group; where R 2 is optionally substituted with 1 or 2 substituents independently selected from F, Cl, Br, I, —CN, —NO 2 , —OH, —CF 3 , —OCF 3 , —OR 8 , C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 haloalkyl, tetrazolyl, C 2 -C 6 heterocycloalkyl, phenyl, -NHS (= O) 2 R 8 , -S (= O) 2 N (R 9 ) 2 , -C (= O) CF 3 , -C (= O) NHS (= O) 2 R 8 , -S (= O) 2 NHC (= O) R 8 , -N (R 9 ) 2 , -N (R 9 ) C (= O) R 8 , -CO 2 R 9 , -C (= O) R 8 , -OC (= O) R 8 , -C (= O) N (R 9 ) 2 , -SR 8 , -S (= O) R 8 and -S (= O) 2 R 8 ; R4 представляет собой арил, возможно замещенный 1 или 2 заместителями, выбранными из F, Cl, Br, I, -CN, -NO2, -СF3, -ОН, -OR8, -ОСF3, C1-С6 алкила, С3-С6 циклоалкила, С1-С6 фторалкила, C1-С6 гетероалкила, C1-С6 галогеноалкила, тетразолила, С2-С6 гетероциклоалкила, фенила, -NHS(=O)2R8, S(=O)2N(R9)2, -С(=O)СF3, -C(=O)NHS(=O)2R8, -S(=O)2NHC(=O)R9, N(R9)2, -N(R9)C(=O)R8, -CO2R9, -C(=O)R8, -OC(=O)R8, -C(=O)N(R9)2, -SR8, -S(=O)R8 и -S(=O)2R8;R 4 is aryl, optionally substituted with 1 or 2 substituents selected from F, Cl, Br, I, —CN, —NO 2 , —CF 3 , —OH, —OR 8 , —OCF 3 , C 1 —C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 fluoroalkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 haloalkyl, tetrazolyl, C 2 -C 6 heterocycloalkyl, phenyl, -NHS (= O) 2 R 8 , S (= O) 2 N (R 9 ) 2 , -C (= O) CF 3 , -C (= O) NHS (= O) 2 R 8 , -S (= O) 2 NHC (= O) R 9 , N (R 9 ) 2 , -N (R 9 ) C (= O) R 8 , -CO 2 R 9 , -C (= O) R 8 , -OC (= O) R 8 , -C (= O) N (R 9 ) 2 , -SR 8 , -S (= O) R 8 and -S (= O) 2 R 8 ; каждый R8 независимо выбран из C1-С6 алкила, C1-С6 галогеноалкила, С3-С8 циклоалкила, фенила и бензилаeach R 8 is independently selected from C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, phenyl, and benzyl каждый R9 независимо выбран из Н, C1-С6 алкила, C1-С6 галогеноалкила, С3-С8 циклоалкила, фенила и бензила.each R 9 is independently selected from H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, phenyl, and benzyl. 12. Способ по п.11, где заболевание, расстройство или состояние у млекопитающего выбрано из заболеваний/расстройств, включающих воспаление, гломерулонефрит, увеит, заболевания или расстройства печени, заболевания или расстройства почек, хроническое обструктивное заболевание легких, ревматоидный артрит, псориаз, воспалительное заболевание кишечника, васкулит, дерматит, остеоартрит, воспалительное заболевание мышц, аллергический ринит, вагинит, интерстициальный цистит, склеродермию, остеопороз, экзему, отторжение трансплантированного органа, аллогенную или ксеногенную трансплантацию, отторжение трансплантата, реакцию «трансплантат против хозяина», красную волчанку, диабет I типа, фиброз легких, дерматомиозит, тиреоидит, тяжелую псевдопаралитическую миастению, аутоиммунную гемолитическую анемию, муковисцидоз, хронический рецидивирующий гепатит, первичный билиарный цирроз, аллергический конъюнктивит, гепатит и атопический дерматит, астму, рассеянный склероз, синдром Шегрена и аутоиммунные заболевания или расстройства.12. The method according to claim 11, where the disease, disorder or condition in a mammal is selected from diseases / disorders including inflammation, glomerulonephritis, uveitis, diseases or disorders of the liver, diseases or disorders of the kidneys, chronic obstructive pulmonary disease, rheumatoid arthritis, psoriasis, inflammatory bowel disease, vasculitis, dermatitis, osteoarthritis, inflammatory muscle disease, allergic rhinitis, vaginitis, interstitial cystitis, scleroderma, osteoporosis, eczema, transplant rejection rejection ana, allogeneic or xenogenic transplantation, transplant rejection, transplant versus host reaction, lupus erythematosus, type I diabetes, pulmonary fibrosis, dermatomyositis, thyroiditis, severe pseudoparalytic myasthenia gravis, autoimmune hemolytic anemia, cystic fibrosis, chronic hepatitis, chronic rehab conjunctivitis, hepatitis and atopic dermatitis, asthma, multiple sclerosis, Sjogren's syndrome and autoimmune diseases or disorders. 13. Способ по п.12, где заболевание, расстройство или состояние представляет собой ревматоидный артрит.13. The method of claim 12, wherein the disease, disorder or condition is rheumatoid arthritis. 14. Способ по п.12, где заболевание, расстройство или состояние представляет собой рассеянный склероз.14. The method of claim 12, wherein the disease, disorder or condition is multiple sclerosis. 15. Способ по п.12, где заболевание, расстройство или состояние представляет собой воспалительное заболевание кишечника. 15. The method of claim 12, wherein the disease, disorder, or condition is an inflammatory bowel disease.
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